title: Inhibition of Snail1-DNA-PKcs protein-protein interface sensitizes cancer cells and inhibits tumor metastasis.
abstract: Our previous study suggested that the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) interacts with Snail1, which affects genomic instability, sensitivity to DNA-damaging agents, and migration of tumor cells by reciprocal regulation between DNA-PKcs and Snail1. Here, we further investigate that a peptide containing 7-amino acid sequences (amino acids 15-21) of Snail1 (KPNYSEL, SP) inhibits the endogenous interaction between DNA-PKcs and Snail1 through primary interaction with DNA-PKcs. SP restored the inhibited DNA-PKcs repair activity and downstream pathways. On the other hand, DNA-PKcs-mediated phosphorylation of Snail1 was inhibited by SP, which resulted in decreased Snail1 stability and Snail1 functions. However, these phenomena were only shown in p53 wild-type cells, not in p53-defective cells. From these results, it is suggested that interfering with the protein interaction between DNA-PKcs and Snail1 might be an effective strategy for sensitizing cancer cells and inhibiting tumor migration, especially in both Snail1-overexpressing and DNA-PKcs-overexpressing cancer cells with functional p53.
authors.affiliation: From the College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750.
authors.forename: Ga-Young
authors.initials: GY
authors.lastname: Kang
authors.affiliation: From the College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750.
authors.forename: Bo-Jeong
authors.initials: BJ
authors.lastname: Pyun
authors.affiliation: the Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul 139-706.
authors.forename: Haeng Ran
authors.initials: HR
authors.lastname: Seo
authors.affiliation: the Korea Atomic Energy Research Institute, Advanced Radiation Technology Institute, Jeongeup-si, Jeollabuk-do 580-185, Korea.
authors.forename: Yeung Bae
authors.initials: YB
authors.lastname: Jin
authors.affiliation: the Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul 139-706.
authors.forename: Hae-June
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: the Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul 139-706.
authors.forename: Yoon-Jin
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: From the College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750,. Electronic address: yslee0425@ewha.ac.kr.
authors.forename: Yun-Sil
authors.initials: YS
authors.lastname: Lee
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D051747:DNA-Activated Protein Kinase / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D010455:Peptides / Q000494:pharmacology*; D055550:Protein Stability / Q000187:drug effects; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D010455:Peptides; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; C497264:Prkdc protein, mouse
keywords: DNA Repair; DNA-PKcs; Migration; Peptides; Phosphorylation; Sensitization; Snail1; Snail1 Phosphorylation; p53